Heart failure is a prevailing disease without effective treatment and represents a significant unmet medical need in the US. In response to pathological stresses, heart undergoes profound remodeling at molecular, cellular and organ levels. In previous studies, we and others have established that a stress-activated protein kinase, p38 plays a significant role in mediating pathological changes in heart under stress. We have demonstrated that constitutive activation of p38 in hearts leads to loss of contractility and pathological remodeling associated with pro- inflammatory cytokine induction. However, we have also observed that genetic inactivation of p38 leads to impaired survival and dysfunction under chronic stress or ageing. This paradox indicates complex roles for p38 mediated signaling in both deleterious and protective mechanisms in heart which has significant implications in the development of p38 targeted therapy for heart failure. To better understand the underlying mechanisms of p38 mediated signaling in heart, we have performed extensive studies at molecular, cellular and functional levels about p38 signaling complex and p38 mediated function. In particular, we have established that the auto-phosphorylation induced non-canonical p38 pathway is regulated by a novel interacting partner, Hsp90/Cdc37 complex. We have also discovered that p38 activity is critical to compensatory vascular remodeling in heart via paracrine cross-talk from cardiomyocytes to endothelial cells. Finally, we have demonstrated that a well established p38 downstream kinase MK2 has a selective contribution to p38 induced pathological changes in heart. These novel findings lead to our current hypothesis that diverse mechanisms in p38 activation and downstream targets contribute to specific roles of p38 signaling in both compensatory and pathological remodeling in heart. In the current proposal, we plan to advance our current knowledge of p38 mediated stress signaling by accomplishing the following specific aims: 1). Determine the molecular mechanism and the functional significance of non-canonical p38 kinase activation in heart. 2). Characterize the mechanisms underlying p38 mediated regulation of cardiomyocyte and endothelium cross-talk during pathological remodeling of heart. 3). Uncover the functional significance of downstream kinase MK2 in p38 mediated stress-response in heart. These studies will significantly advance our current knowledge in the disease mechanisms of heart failure and help to develop more effective therapy for the disease. PUBLIC HEALTH RELEVANCE: Stress kinase p38 is an important signaling pathway in stress-response. Our proposal will investigate the molecular mechanisms and functional role of a novel non-canonical activation pathway of p38 and its impact on crosstalk from myocyte to endothelial cells. These studies will improve our current understanding to the disease mechanisms of heart failure and provide potential insights for development of better treatment.